Communication pubs.acs.org/JACS
Stereospecific Intramolecular Reductive Cross-Electrophile Coupling Reactions for Cyclopropane Synthesis Emily J. Tollefson, Lucas W. Erickson, and Elizabeth R. Jarvo* Department of Chemistry, University of California, Irvine, California 92697-2025, United States S Supporting Information *
Scheme 1. Asymmetric Reductive Cross-Electrophile Coupling Strategies
ABSTRACT: The stereospecific reductive cross-electrophile coupling reaction of 2-aryl-4-chlorotetrahydropyrans to afford disubstituted cyclopropanes is reported. This ring contraction presents surprises with respect to the stereochemical outcome of reaction of the alkyl halide moiety. While cross-coupling and reductive cross-electrophile coupling reactions of alkyl halides are typically stereoablative, using a chiral catalyst to set the stereocenter, this transformation proceeds with high stereochemical fidelity at the alkyl halide and ether bearing stereogenic centers. This approach provides straightforward access to highly substituted cyclopropanes in two steps from commercially available aldehydes. or miners and organometallic chemists “the devil’s copper” can provide intrigue and vexation.1 In addition to providing inexpensive alternatives to precious palladium catalysts, nickel complexes present a diverse range of elementary reactions, including both polar and single-electron chemistry.2 Indeed, mechanistic ambiguity has been a challenge in rational design of new catalytic transformations. At the same time, the unique reactivity patterns offered by Ni catalysts can provide advantages in certain settings. For example, Ni catalysts are particularly well suited for reactions employing alkyl halides and pseudohalides, due to their ability to engage sluggish electrophilic partners and reduced propensity for β-hydride elimination.3 For these reasons, Ni catalysts have been critical for development of cross-coupling reactions of alkyl electrophiles and in recent development of reductive cross-electrophile coupling reactions.4 In a reductive cross-electrophile coupling reaction, two electrophilic partners, typically alkyl or aryl halides, are coupled in the presence of exogenous reducing agent. This strategy circumvents synthesis of an organometallic reagent, as would be required for a traditional cross-coupling reaction.4 Weix et al. pioneered the Ni-catalyzed reductive cross-coupling of aryl and alkyl halides with a variety of electrophilic partners (Scheme 1A).5 Recently, they reported cross-electrophile coupling of benzylic alcohols and benzylic chlorides with aryl halides.6 Reisman et al. reported stereoconvergent reductive crosscoupling reactions of racemic benzylic chlorides with acid chlorides or vinyl bromides to provide products with good yield and high ee (Scheme 1B).7 Stereoconvergent methods capitalize on the stereoablative nature of oxidative addition of Ni complexes with alkyl halides and employ a chiral ligand to set the desired stereocenter.8
F
© XXXX American Chemical Society
Recent work in our laboratory demonstrated Ni-catalyzed stereospecific cross-coupling reactions of alkyl ethers and esters under Kumada, Negishi, and Suzuki-type conditions.9 We hypothesized that these electrophiles would also participate in stereospecific cross-electrophile coupling reactions, since oxidative addition of the low-valent Ni catalyst with the benzylic ether should be a common elementary step in both mechanisms. Here we report the stereospecific ring contractions of 2-aryl-4chlorotetrahydropyrans to afford substituted cyclopropanes (Scheme 1C), via an intramolecular reductive cross-coupling reaction10 of a benzylic ether and an alkyl halide. Notably, it is strictly stereospecific with respect to both electrophilic functional groups. As anticipated at the outset, oxidative addition at the benzylic ether proceeds with high stereochemical fidelity.9a One surprising feature of this transformation is that the alkyl halide bearing stereogenic center reacts with high stereospecificity (vide infra). This result is unusual, as prior Ni-catalyzed reactions of alkyl halides were stereoablative.8 In addition to affording a stereospecific cross-electrophile coupling, this reaction provides straightforward and scalable access to substituted cyclopropanes, important organic motifs found in many natural products and medicinal agents.11 The strained nature and reactivity of cyclopropanes make them valuable synthetic intermediates and mechanistic probes, and as such the development of their asymmetric synthesis has been an area of intensive research.12 By effecting a skeletal rearrangement of the tetrahydropyran starting material, this reductive crosscoupling reaction provides cyclopropanes bearing a synthetic Received: April 14, 2015
A
DOI: 10.1021/jacs.5b03870 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Communication
Journal of the American Chemical Society handle appropriate for further functionalization as part of targetor diversity-oriented synthetic strategies. To test our hypothesis for a stereospecific ring contraction, we designed test substrate tetrahydropyran cis-8. As a starting point, we examined this substrate under the same catalyst conditions we employed in our previous Kumada-type cross-coupling reactions of aryl-substituted tetrahydropyrans.9a Using a combination of Ni(cod)2 and rac-BINAP, in the presence of MeMgI, we found that cis-8 afforded cis-9 in excellent yield and as a single diastereomer (Table 1, entry 1). The relative configuration of 9 was assigned as cis by X-ray crystallographic analysis of a derivative and NOE NMR experiments.13
With optimized reaction conditions in hand, we next examined the stereospecificity of the reaction. Because Ni-catalyzed reactions using alkyl halides are typically stereoconvergent and are thought to proceed through alkyl radical intermediates, we were interested in determining whether cis- and trans-8 would afford the same diastereomer of product and whether use of a chiral ligand would influence the diastereomeric ratio. We subjected both cis- and trans-8 to reactions employing rac-BINAP and were surprised to see that the reaction was not stereoconvergent, but was highly stereospecific with respect to the alkyl halide (Table 2). Chloride cis-8 afforded cis-9 in high yield and Table 2. Substrate Control of Stereochemistry
Table 1. Optimization of Reaction Conditions
a Isolated yield after column chromatography. bDetermined by 1H NMR. Nap = 2-naphthyl. a
Yield determined by 1H NMR based on comparison to PhTMS as internal standard. bAll reagents were weighed on the benchtop, and the reaction was purged with N2 before addition of MeMgI.
excellent dr (entry 1). Similarly, trans-8 yielded trans-9 with high yield and dr (entry 4). Introduction of enantioenriched catalyst does not perturb the high level of stereospecificity: in all cases, the reaction occurred cleanly with inversion at the benzylic ether and retention at the alkyl halide bearing a stereogenic center (entries 2, 3, 5, and 6). These results are not consistent with initiating the reaction by oxidative addition of the alkyl halide moiety.17 This stereochemical outcome in the reaction of an alkyl halide with a low-valent Ni complex is unusual and has significant implications for the mechanism of this transformation, which is currently under investigation. To determine whether the reaction proceeds with net inversion or retention at the reactive centers, we prepared enantioenriched trans-8.18 As anticipated, ring contraction proceeded with high enantiospecificity (es; eq 1).19 Product 9 was derivatized, and absolute configuration was assigned by X-ray crystallographic analysis.13 Surprisingly, we found that reaction at the benzylic ether occurred with net retention.20 The alkyl chloride moiety reacted with inversion. While this stereochemical outcome is unexpected, it appears to be consistent in this ring contraction (vide infra).
To determine what components of the reaction were necessary, we examined both the Ni catalyst and the Grignard reagent. We first removed Ni(cod)2 and rac-BINAP from the reaction and saw no conversion of the starting material, indicating the reaction is indeed Ni-catalyzed (entry 2). We found that catalyst loadings as low as 2.5 mol% resulted in full conversion to product in 24 h at rt (entry 3). Other bidentate phosphine ligands, such as DPEphos, were not as effective in the reaction (entry 4). We also examined alternative Ni precatalysts. We found that Ni(acac)2, a more stable Ni precatalyst, provided lower conversion than Ni(cod)2 (entry 5). However, with the addition of 12 mol% of 1,5-cyclooctadiene conversion to product is restored (entry 6). This catalyst system is also amenable to set up on the benchtop, avoiding use of a glovebox (entry 7). Based on our previous development of Ni-catalyzed alkylHeck reactions, we hypothesized that the Grignard reagent acts as a reducing agent to effect catalyst turnover.14 Removing the Grignard reagent resulted in full recovery of starting material; using only 1 equiv resulted in 54% yield (entries 8 and 9, respectively).15 Use of commercial MeMgBr affords 80% yield of 9 (entry 10). We found that the identity of the Grignard reagent was not crucial. Switching to PhMgBr from MeMgI had no detrimental effect (entry 11). Using PhMgBr, we also isolated 1 equiv of biphenyl side product, supporting our hypothesis that the Grignard reagent acts to reduce the Ni catalyst. Unfortunately, after examining milder reducing agents, e.g., dimethylzinc or manganese powder, we found that a Grignard reagent is required in order for the reaction to proceed (entry 12). While this is not an ideal reducing agent, it is readily available and straightforward to handle.16
We envisioned that this reaction would provide a robust and scalable strategy to synthesize single diastereomers of cyclopropanes from commercially available aldehydes. To demonstrate that this strategy is amenable to larger scale, we performed the two-step sequence on a 5.3 mmol scale (Scheme 2). Prins cyclization of 10 with 3-buten-1-ol employing ZnCl2 and p-TSA proceeded smoothly to afford cis-8 in 80% yield and 20:1 dr.21 B
DOI: 10.1021/jacs.5b03870 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Communication
Journal of the American Chemical Society Scheme 2. Amenability to Scale Up
Table 4. Scope of Trisubtituted Tetrahydropyrans
With 1 g of cis-8 in hand, we determined that ring contraction with only 1 mol% catalyst provides cis-9 in 93% yield and 20:1 dr. This strategy provides a straightforward method for conversion of the requisite aldehyde to the cyclopropane in two steps and with reliable control of relative stereochemistry. Having established the robustness of this reaction, we turned our attention to determining the scope. We examined a range of aryl-substituted tetrahydropyrans (Table 3). Reactions of Table 3. Scope of Ring Contraction Reaction
a
Isolated yield after column chromatography. bReported as (cis:trans) determined by 1H NMR. cReaction performed without addition of MgI2 and with 5 mol% catalyst loading. Nap = 2-naphthyl.
1 equiv of MgI2 afforded cyclopropane 24 in 88% yield and >99% es (entry 1). In related Kumada-type cross-coupling reactions, we observed that MgI2 accelerates reactions of sluggish substrates.22 We hypothesize that the Lewis acidic salts coordinate the benzylic ether, facilitating oxidative addition of the C−O bond. Derivatization and X-ray crystallographic analysis demonstrated that the reaction occurred with retention at the benzylic ether and inversion at the alkyl chloride.13 This stereochemical outcome is consistent with our earlier observations (eq 1). Adding MgI2 also resulted in good conversion of 25, with a larger substituent at the C6 position, to 26 (entry 2). To challenge the reaction, we examined if substitution at the reactive centers would be tolerated. The use of tertiary chloride 27 afforded 28, containing a quaternary center, in 62% yield and good transfer of stereochemical information (entry 3). In beginning to examine the broader scope, we set out to determine if the tetrahydropyran scaffold was integral to reactivity. We first examined a smaller cyclic ether, tetrahydrofuran 29. Subjecting tetrahydrofuran cis-29 to the reaction afforded cis-30 in 87% and 20:1 dr (Scheme 3a), indicating that Scheme 3. Application to Alternative Substrate Classes a
b
Isolated yield after column chromatography. Determined by 1H NMR. cReaction performed on a 1.0 mmol scale.
benzofuran- and benzothiophene-substituted tetrahydropyrans proceed in good yields and dr (entries 1−3). In an effort to challenge the transformation, we examined simple furancontaining substrates 15 and 17. Both 2- and 3-substituted furans yielded desired product in excellent yield and with transfer of stereochemical information (entries 4 and 5). We found that 6-methoxy-2-naphthalene substituted THP cis-19 proceeded in 97% yield and 20:1 dr and was amenable to a larger 1.0 mmol scale reaction (entries 6 and 7). Reaction of trans-19 likewise proceeded with clean transfer of stereochemical information to afford trans-20 in 97% yield (entry 8). To synthesize cyclopropanes with a more complex range of substituent patterns, we examined a series of trisubstituted tetrahydropyrans (Table 4). Subjecting enantioenriched 2,4,6trisubstituted tetrahydropyran 23 to the standard reaction conditions resulted in only partial conversion. However, adding
decreasing the carbon tether is not detrimental to the reaction. We were also interested if an unstrained, acyclic scaffold would provide substrates that are competent in the reaction. We subjected primary chloride 31 to standard reaction conditions (Scheme 3b). Cyclopropane 32 was obtained in 71%, indicating that acyclic primary chlorides are indeed tolerated. As our reaction is amenable to cyclopropanes bearing simple heteroaromatic rings, we sought to exploit these functional groups to obtain alkyl-substituted cyclopropanes. Kobayashi et al. demonstrated that 2-substituted furans can be oxidized to form 2-enonic acids.23 This functionality translates nicely as a C
DOI: 10.1021/jacs.5b03870 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Communication
Journal of the American Chemical Society
cross-coupling of an alkyl tosylate with aryl bromide: Liu, J.-H.; Yang, C.T.; Lu, X.-Y.; Zhang, Z.-Q.; Xu, L.; Cui, M.; Lu, X.; Xiao, B.; Fu, Y.; Liu, L. Chem. - Eur. J. 2014, 20, 15334. (7) (a) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 7442. (b) Cherney, A. H.; Reisman, S. E. J. Am. Chem. Soc. 2014, 136, 14365. (8) (a) Stille, J. K.; Cowell, A. B. J. Organomet. Chem. 1977, 124, 253. (b) Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc. 1979, 101, 7547. (c) Jones, G. D.; Martin, J. L.; McFarland, C.; Allen, O. R.; Hall, R. E.; Haley, A. D.; Brandon, R. J.; Konovalova, T.; Desrochers, P. J.; Pulay, P.; Vicic, D. A. J. Am. Chem. Soc. 2006, 128, 13175. (d) Lin, X.; Phillips, D. L. J. Org. Chem. 2008, 73, 3680. (e) Castaño, A. M.; Echavarren, A. M. Organometallics 1994, 13, 2262. (f) Phapale, V. B.; Bunuel, E.; García-Eglesias, M.; Cárdenas, D. J. Angew. Chem., Int. Ed. 2007, 46, 8790. (g) Schley, N. D.; Fu, G. C. J. Am. Chem. Soc. 2014, 136, 16588. (h) Biswas, S.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 16192. Formation of an alkyl radical during oxidative addition is not the only mechanism by which a stereoablative reaction can occur: (i) Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2002, 124, 4222. (j) Gutierrez, O.; Tellis, J. C.; Primer, D. N.; Molander, G. A.; Kozlowski, M. C. J. Am. Chem. Soc. 2015, 137, 4896. (9) (a) Tollefson, E. J.; Dawson, D. D.; Osborne, C. A.; Jarvo, E. R. J. Am. Chem. Soc. 2014, 136, 14951. (b) Tollefson, E. J.; Hanna, L. E.; Jarvo, E. R. Acc. Chem. Res. 2015, DOI: 10.1021/acs.accounts.5b00223. (10) Synthesis of cyclopentanes by Ni-catalyzed reductive coupling: Xue, W.; Xu, H.; Liang, Z.; Qian, Q.; Gong, H. Org. Lett. 2014, 16, 4984. (11) (a) Salaun, J. In Topics in Current Chemistry; de Meijere, A., Ed.; Springer-Verlag: Berlin, 2000; Vol. 207, pp 1−66. (b) Chen, D. Y.-K.; Pouwer, R. H.; Richard, J.-A. Chem. Soc. Rev. 2012, 41, 4631. (12) (a) A review: Bartoli, G.; Bencivenni, G.; Renato, D. Synthesis 2014, 46, 979. (b) Ring-contraction of dihydropyrans via [1,4]-Wittig rearrangement: Mori-Quiroz, L. M.; Maleczka, R. E. J. Org. Chem. 2015, 80, 1163. (c) Engineered P450 for enantioselective cyclopropanation: Coehlo, P. S.; Brustad, E. M.; Kannan, A.; Arnold, F. H. Science 2013, 339, 307. (13) See Supporting Information for details. (14) Harris, M. R.; Konev, M. O.; Jarvo, E. R. J. Am. Chem. Soc. 2014, 136, 7825. (15) Replacing Grignard reagent with 2 equiv of MgI2 resulted in no conversion of 8, consistent with a required terminal reducing agent. (16) Failure of alternative reducing agents is consistent with transmetalation of the Grignard reagent prior to oxidative addition of benzylic ether. (17) (a) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340. (b) For stereoconvergent cross-coupling reactions of these substrates, see ref 9a.
building block to prepare biologically active scaffolds, such as halicholactone, a lipoxygenase inhibitor, and its family members.24 We envisioned that our method could be used to synthesize analogs of this class of natural products. 2-Furansubstituted cyclopropane cis-33 was oxidized using the reported conditions (Scheme 4). 2-Enonic acid 34 was obtained in 66% yield with no loss of stereochemistry. Scheme 4. Oxidation of Furan 33
In summary, stereospecific synthesis of di- and trisubstituted cyclopropanes is achieved via a Ni-catalyzed reductive crosselectrophile coupling of 2-aryl-4-chlorotetrahydropyrans. The ring contraction is stereospecific with respect to both the benzylic ether and the alkyl halide moieties. Efforts to expand the scope and elucidate the mechanism of the transformation are underway.
■
ASSOCIATED CONTENT
S Supporting Information *
Experimental details and characterization data. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.5b03870. For crystallographic data see also CCDC 1059382, 1413565, and 1414041.
■
AUTHOR INFORMATION
Corresponding Author
*
[email protected] Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This work was supported by NSF-CHE-1464980 and the University of California (Chancellor’s Fellowship and Graduate Opportunity Fellowship to E.J.T.). We acknowledge Dr. Joseph Ziller for X-ray crystallographic data and Dr. John Greaves for mass spectrometry data.
■
REFERENCES (18) See SI for details. Yadav, J. S.; Subba Reddy, B. V.; Padmavani, B.; Venugopal, Ch.; Bhaskar Rao, A. Tetrahedron Lett. 2007, 48, 4631. (19) Enantioselectivity: Denmark, S. E.; Vogler, T. Chem. - Eur. J. 2009, 15, 11737. (20) In our experience, cross-coupling reactions of benzylic ethers, including tetrahydropyrans, occurs with inversion (ref 9a). Suzuki coupling of benzylic esters can proceed with retention or inversion: (a) Harris, M. R.; Hanna, L. E.; Greene, M. A.; Moore, C. E.; Jarvo, E. R. J. Am. Chem. Soc. 2013, 135, 3303. (b) Zhou, Q.; Srinivas, H. D.; Dasgupta, S.; Watson, M. P. J. Am. Chem. Soc. 2013, 135, 3307. (21) (a) Borkar, P.; van de Weghe, P.; Reddy, B. V. S.; Yadav, J. S.; Grée, R. Chem. Commun. 2012, 48, 9316. (b) Pastor, I. M.; Yus, M. Curr. Org. Chem. 2012, 16, 1277. (22) Greene, M. A. Ph.D. Thesis, University of California, Irvine, May 2013. (23) Kobayashi, Y.; Nakano, M.; Kumar, G. B.; Kishihara, K. J. Org. Chem. 1998, 63, 7505. (24) (a) Niwa, H.; Wakamatsu, K.; Yamada, K. Tetrahedron Lett. 1989, 30, 4543. (b) Proteau, P. J.; Rossi, J. V.; Gerwick, W. H. J. Nat. Prod. 1994, 57, 1717.
(1) Modern Organonickel Chemistry; Tamaru, Y., Ed.; Wiley-VCH: Weinhein, 2005. (2) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Nature 2014, 509, 299. (3) For a discussion, see: (a) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417. (b) Hu, X. Chem. Sci. 2011, 2, 1867. (c) Netherton, M. R.; Fu, G. C. Adv. Synth. Catal. 2004, 346, 1525. (4) (a) Knappke, C. E. I.; Grupe, S.; Gärtner, D.; Corpet, M.; Gosmini, C.; von Wangelin, A. J. Chem. - Eur. J. 2014, 20, 6828. (b) Everson, D. A.; Weix, D. J. J. Org. Chem. 2014, 79, 4793. (5) (a) Everson, D. A.; Shrestha, R.; Weix, D. J. J. Am. Chem. Soc. 2010, 132, 920. (b) Everson, D. A.; Jones, B. A.; Weix, D. J. J. Am. Chem. Soc. 2012, 134, 6146. (c) Anka-Lufford, L. L.; Prinsell, M. R.; Weix, D. J. J. Org. Chem. 2012, 77, 9989. See the following for cross-electrophile coupling of epoxides with aryl bromides. (d) Stereospecific: Zhao, Y.; Weix, D. J. J. Am. Chem. Soc. 2014, 136, 48. (e) Stereoconvergent: Zhao, Y.; Weix, D. J. J. Am. Chem. Soc. 2015, 137, 3237. (f) Review of crosscoupling reactions of epoxides: Huang, C.-Y.; Doyle, A. G. Chem. Rev. 2014, 114, 8153. (6) (a) Ackerman, L. K. G.; Anka-Lufford, L. L.; Naodovic, M.; Weix, D. J. Chem. Sci. 2015, 6, 1115. (b) Cu-catalyzed stereospecific reductive D
DOI: 10.1021/jacs.5b03870 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
